Occupational Exposures and Risks of Non-Hodgkin Lymphoma: A Meta-Analysis

Simple Summary It is unclear what causes the increased incidence of non-Hodgkin lymphoma (NHL); however, chemical substance exposure is known to be one of the risk factors for the disease. The aim of our systematic review was to verify the association between occupational exposure to carcinogens and NHL risk. In our literature review, 51 articles were included in the meta-analysis resulting in an overall OR of 1.27 (95% CI 1.04–1.55). Among these studies, 20 reported a significant association with the increased risk of NHL. We demonstrate that the risk of NHL increases for individuals occupationally exposed to pesticides, benzene, and trichloroethylene. Our findings may provide information for public health and practical decision-making about certain work activities and the use of chemical compounds. Abstract Non-Hodgkin lymphoma (NHL) is a heterogeneous group with different types of diseases. It remains unclear as to what has led to an increase in incidences of NHL, however, chemical substance exposure is known to be one of the risk factors for the disease. Therefore, we performed a systematic review and meta-analysis including case-control, cohort, and cross-sectional observational epidemiological studies to verify the association between occupational exposure to carcinogens and NHL risk. Articles between the years 2000 and 2020 were collected. Two different reviewers performed a blind selection of the studies using the Rayyan QCRI web app. Post-completion, the selected articles were extracted and analyzed via the RedCap platform. Our review resulted in 2719 articles, of which 51 were included in the meta-analysis, resulting in an overall OR of 1.27 (95% CI 1.04–1.55). Furthermore, it was observed that the main occupation associated with the increased risk of NHL was that in which workers are exposed to pesticides. We therefore conclude that the evidence synthesis of the epidemiological literature supports an increased risk for NHL, regardless of subtype, considering occupational exposure to certain chemical compounds, mainly pesticides, benzene, and trichlorethylene, and certain classes of work, primarily in the field of agriculture.


Introduction
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of diseases that stem from the proliferation of malignant lymphocytes and their precursors. These cells accumulate in the lymph nodes, but can also extend to other organs [1,2]. There are different subtypes of NHL, often with variations in their presentations, prognoses, and clinical treatments [3]. NHL ranks as the eighth and tenth most frequent cancer among men and After the initial screening step, the entire text of the articles, which may contain relevant information, was reviewed by the two reviewers. The following information was extracted from the eligible articles: authorship, year of publication, country of publication and study, study design, population, gender of participants, diagnosis, occupational activity, chemical agent, sample size, number of exposed and non-exposed individuals (cohort and crosssectional studies), number of case and control (case-control study), number of exposed individuals who developed NHL, and outcome measures. The RedCap web platform was used for data extraction by both reviewers and tabulated electronically. During each step, the results were compared, and any discrepancies were clarified with the participation of a third reviewer.

Quality Assessment
Study quality assessment was carried out using the Study Quality Assessment Tool, developed by methodologists at the National Heart, Lung, and Blood Institute (NHLBI), in conjunction with professionals at the Research Triangle Institute International. The tool was based on other assessment tools created by the Evidence Based Practice Centers of the Agency for Healthcare Research and Quality (AHRQ), Cochrane, the Scottish Intercollegiate Guidelines Network and, others working in the context of evidence-based medicine. Designed to assist reviewers, the tool was considered, for this research, fundamental to the critical evaluation of the internal validity of a study. This includes items to assess potential flaws in study methods, including risks of bias.
During the quality review of the studies, each item of the tool may be answered with a "yes", "no", or "cannot be determined/not reported/not applicable". For each item in which "no" was selected, a potential risk of bias was considered. This assessment tool is not designed to provide a list of factors that make up a numerical score or to delimit a score for reviewers. Thus, it is used, by following with the literature, for intervention studies, a rating of bad ≤ 6, regular > 6 and 5, and good ≥ 10 is used. For case-control studies that contained 12 questions instead of 14, the rating was adjusted: bad ≤ 5, regular > 5, and <9, and good ≥ 9 [26].

Data Analysis of the Systematic Review
Results from the cohort, cross-sectional, and case-control studies that associated exposure to chemical compounds or work class with increased risk of NHL were included in the meta-analysis. The meta-analysis was performed for each comparison using the random effects model, and the OR with the 95% Confidence Interval (CI) was calculated using the Mantel Haenszel method. The combined OR (ψ MH ) was estimated by adding together the individual ORs (ψ k ) from each study according to the expression of [27]: where: w k = (b k c k )/n k K = total number of studies k = 1, 2, . . . , K ψ k = (a k d k )/(b k c k ) n k = study sample size k a k = number of events in the group exposed in the study k b k = number of non-events in the group exposed in the study k c k = number of events in the unexposed group in the study k d k = number of non-events in the non-exposed group in the study k n k = sample size (all studies) Variables included in the meta-analysis were sample size, number of exposed individuals, number of non-exposed individuals, number of exposed individuals with an event, and Cancers 2023, 15, 2600 4 of 19 non-exposed individuals with an event. Heterogeneity between each study was estimated using the Q-statistic of the Q-Cochran test and quantified using the inconsistency index (I 2 ) [28]. Funnel plot was used to assess potential publication bias [29]. Analyses were performed using R version 4.1.2 (1 November 2021) software, using the functions metabin, forest.meta, and funnel from the package meta.

Characterization of the Studies
The search of the database resulted in 2719 articles. Duplicate and irrelevant articles were excluded as described in the inclusion criteria. A total of 537 duplicate articles were excluded while the remaining 2182 were selected for evaluation based on titles and abstracts. Evaluation of the titles and abstracts revealed that 1854 articles did not analyze the association between occupations and carcinogens with the increased risk of NHL. As a result, an additional 1854 articles were excluded. The remaining 328 articles were subjected to a full-text review; of these, 27 articles did not meet the inclusion criteria. During data extraction, 129 articles were excluded by methodological evaluation, as a result, only 172 remained eligible for the study. Ultimately, 51 articles were included in the meta-analysis, because 121 articles did not present the necessary information for the calculation of the effect size (Odd Ratio) ( Figure 1). Variables included in the meta-analysis were sample size, number of exposed individuals, number of non-exposed individuals, number of exposed individuals with an event, and non-exposed individuals with an event. Heterogeneity between each study was estimated using the Q-statistic of the Q-Cochran test and quantified using the inconsistency index (I 2 ) [28]. Funnel plot was used to assess potential publication bias [29]. Analyses were performed using R version 4.1.2 (1 November 2021) software, using the functions metabin, forest.meta, and funnel from the package meta.

Characterization of the Studies
The search of the database resulted in 2719 articles. Duplicate and irrelevant articles were excluded as described in the inclusion criteria. A total of 537 duplicate articles were excluded while the remaining 2182 were selected for evaluation based on titles and abstracts. Evaluation of the titles and abstracts revealed that 1854 articles did not analyze the association between occupations and carcinogens with the increased risk of NHL. As a result, an additional 1854 articles were excluded. The remaining 328 articles were subjected to a full-text review; of these, 27 articles did not meet the inclusion criteria. During data extraction, 129 articles were excluded by methodological evaluation, as a result, only 172 remained eligible for the study. Ultimately, 51 articles were included in the meta-analysis, because 121 articles did not present the necessary information for the calculation of the effect size (Odd Ratio) ( Figure 1). The systematic review comprised 76 case-control articles and 96 cohort/transversal articles. In regards to geographic coverage, of the 172 articles included in this review, 74 studies were conducted in the United States, 17 in Canada, 14 in France, 13 in Italy and Sweden, 10 in Germany and Spain, 9 in Denmark and Norway, 7 in China and the United Kingdom, 6 in Australia, New Zealand, and the Czech Republic, 5 in Finland and Ireland, 4 in Japan, 3 in Brazil, England, and Iceland, 2 in Korea, Greece, the Netherlands, and Iran, 1 in South Africa, Singapore, Poland, Taiwan, and Ukraine ( Figure 2).
Several studies conducted at these locations are cohort studies or are part of consortia. The Agricultural Health Study (AHS) was the main cohort study evaluated in the studies [30][31][32][33][34][35][36][37][38][39][40][41][42]. The AHS is a prospective study of licensed pesticide applicators and their spouses in Iowa and North Carolina (USA), designed to understand how agricultural, lifestyle, and genetic factors affect the health of agricultural populations. The International Lymphoma Epidemiology Consortium (InterLymph) was found to have the largest number of studies among the consortia analyzed for this review [8,13,14,18,[43][44][45]. The InterLymph Consortium conducts research through case-control studies in non-Hodgkin lymphoma addressing genetics, immunity and infection, lifestyle and environment, pathology, and Several studies conducted at these locations are cohort studies or are part of consortia. The Agricultural Health Study (AHS) was the main cohort study evaluated in the studies [30][31][32][33][34][35][36][37][38][39][40][41][42]. The AHS is a prospective study of licensed pesticide applicators and their spouses in Iowa and North Carolina (USA), designed to understand how agricultural, lifestyle, and genetic factors affect the health of agricultural populations. The International Lymphoma Epidemiology Consortium (InterLymph) was found to have the largest number of studies among the consortia analyzed for this review [8,13,14,18,[43][44][45]. The Inter-Lymph Consortium conducts research through case-control studies in non-Hodgkin lymphoma addressing genetics, immunity and infection, lifestyle and environment, pathology, and survival. These types of studies have contributed greatly over the years to the understanding of the association between environmental/occupational exposure and the development of diseases such as non-Hodgkin lymphomas.
The association between a large number of work classes and chemical compounds associated with the development of NHL and its subtypes has not been evaluated in any review. Reviews typically evaluate the association between the increased risk of overall NHL or some specific subtype with only one group of chemical agents or work class [21,22,46,47]. In our review, the following occupations: painter, driver, construction worker, hairdresser, chemical industry employee, solvent-exposed employees, agricultural mechanics and laborers, husbandry workers, and fishing laborers were the most The association between a large number of work classes and chemical compounds associated with the development of NHL and its subtypes has not been evaluated in any review. Reviews typically evaluate the association between the increased risk of overall NHL or some specific subtype with only one group of chemical agents or work class [21,22,46,47]. In our review, the following occupations: painter, driver, construction worker, hairdresser, chemical industry employee, solvent-exposed employees, agricultural mechanics and laborers, husbandry workers, and fishing laborers were the most investigated work classes used in the studies included in the review. In terms of the chemical compounds investigated in the studies, the most frequently evaluated were pesticides, radiation, solvents, hydrocarbons, metals, organic compounds, asbestos, paints, petroleum products, and organochlorines.

Characteristics of the Studies Included in the Meta-Analysis
A total of 51 observational studies that met our inclusion criteria were identified and included in the meta-analysis. Accordingly, 28 case-control studies and 23 cohort studies were included. Table 1 shows an evaluated summary of the data extracted from each study, including author and year of publication, site, study design, exposure categories (work class and carcinogen), NHL subtype, and OR. Given the types of exposures present in the articles, the primary class of work evaluated in the articles, as part of the meta-analysis, was agricultural occupation and related activities. The main chemical agents analyzed were pesticides and solvents. When analyzing the NHL subtypes evaluated in the articles, of the 51 articles included in the meta-analysis, 22 evaluated the risk of Chronic Lymphocytic Leukemia/Small Cell Lymphocytic Lymphoma (CLL/SLL), 20 of Multiple Myeloma (MM), 17 of Follicular Lymphoma (FL) and Diffuse Large B Cell Lymphoma (DLBCL), and 6 of B cell in general. Although these were the most commonly investigated subtypes in the articles included in the meta-analysis, other subtypes of NHL were also evaluated as noted in Table 1.  The meta-analysis of the 51 studies produced an overall OR of 1.27 (95% CI 1.03-1.55). This suggests that some work classes and occupational exposure to certain compounds are associated with a 27% increase in the risk of NHL. The highest OR entered was for the study by Mahajan et al. [38] (OR = 14.67), in which they assessed exposure to pesticides. The lowest was for the study by Rusiecki et al. [41] (OR = 0.08), in which they assessed individuals in agricultural occupations. No individual study received more than 3% of the total weight assigned in the random effects model (Figure 3). The random effects model yielded a heterogeneity value of 93% with p < 0.01, indicating significant heterogeneity across studies (Figures 3 and S1). The meta-analysis of the 51 studies produced an overall OR of 1.27 (95% CI 1.03-1.55). This suggests that some work classes and occupational exposure to certain compounds are associated with a 27% increase in the risk of NHL. The highest OR entered was for the study by Mahajan et al. [38] (OR = 14.67), in which they assessed exposure to pesticides. The lowest was for the study by Rusiecki et al. [41] (OR = 0.08), in which they assessed individuals in agricultural occupations. No individual study received more than 3% of the total weight assigned in the random effects model (Figure 3). The random effects model yielded a heterogeneity value of 93% with p < 0.01, indicating significant heterogeneity across studies (Figures 3 and S1). Altogether, more than 20 different work classes and more than 30 chemical compounds were evaluated (Table 1). Of the 20 studies that exhibited significant OR, most (14 studies) evaluated individuals in the agricultural occupation, or occupationally exposed to pesticides. As for the carcinogenic potential of the compounds most evaluated in the articles that were included in the meta-analysis, pesticides present varied carcinogenicity Altogether, more than 20 different work classes and more than 30 chemical compounds were evaluated (Table 1). Of the 20 studies that exhibited significant OR, most (14 studies) evaluated individuals in the agricultural occupation, or occupationally exposed to pesticides. As for the carcinogenic potential of the compounds most evaluated in the articles that were included in the meta-analysis, pesticides present varied carcinogenicity classifi-cations, given that the classification depends greatly on the active compound evaluated. The only pesticide analyzed in the articles that were included in the meta-analysis that is classified as carcinogenic for humans (Group 1), according to the International Agency for Research on Cancer [86], is Lindane, which exhibited sufficient evidence of carcinogenicity for non-Hodgkin lymphoma [50].
Although pesticides constitute the main exposure evaluated in the articles, four of the 20 articles that revealed significant OR had evaluated exposure to solvents, formaldehyde, trichloroethylene, and benzene, which were the main compounds analyzed in these articles. In addition, significant OR was also observed for studies that evaluated employees in the manufacture and operation of aircraft, employees exposed to meat, and factory workers exposed to benzene (Table 1). Formaldehyde, trichloroethylene, and benzene solvents are considered carcinogenic to humans according to the IARC classification based on the results of epidemiological studies [86].
Given the high heterogeneity observed in our meta-analysis, we carried out subgroup analyses as an approach to identify the potential sources of heterogeneity in our overall meta-effects estimate. Thus, combined estimates of studies by NHL subtype, experimental design types, and exposure types were conducted. In the analysis performed for each NHL subtype evaluated in more than three studies, included in our meta-analysis, a meta-OR above 1.0 with significance for the random effects model was only observed for the DLBCL (OR 1.13, 95% CI 1.04-1.23) (Figures 4A and S2).
hyde, trichloroethylene, and benzene, which were the main compounds analyzed in these articles. In addition, significant OR was also observed for studies that evaluated employees in the manufacture and operation of aircraft, employees exposed to meat, and factory workers exposed to benzene (Table 1). Formaldehyde, trichloroethylene, and benzene solvents are considered carcinogenic to humans according to the IARC classification based on the results of epidemiological studies [86].
Given the high heterogeneity observed in our meta-analysis, we carried out subgroup analyses as an approach to identify the potential sources of heterogeneity in our overall meta-effects estimate. Thus, combined estimates of studies by NHL subtype, experimental design types, and exposure types were conducted. In the analysis performed for each NHL subtype evaluated in more than three studies, included in our meta-analysis, a meta-OR above 1.0 with significance for the random effects model was only observed for the DLBCL (OR 1.13, 95% CI 1.04-1.23) (Figures 4A and S2).
The most frequent subtype of non-Hodgkin lymphoma worldwide is DLBCL which presents as a heterogeneous disease group with variable outcomes [87]. In our meta-analysis, the individual studies that showed a significantly increased risk of DLBCL (OR > 1), analyzed populations exposed to solvents (benzene, formaldehyde, chloroform, carbon tetrachloride, dichloromethane, dichloroethane, and methyl chloride) [64,70] and hair dyes [66]. In addition, one study carried out their investigations with meat handlers, people in contact with meat and meat products in general (contact with beef, chicken, pork, lamb, meat from other animals and fish), [73] and another study with the agricultural occupations (farm workers and cattle or animal breeders) [66] (Figure 4B). Few meta-analysis studies separately assess the DLBCL subtype associated with any given type of exposure. One of the compounds evaluated by the articles that showed significant OR in our meta-analysis for the DLBCL subtype was benzene. Rana et al. [88] found an association between benzene exposure and an increased risk of DLBCL in their meta-analysis.  The most frequent subtype of non-Hodgkin lymphoma worldwide is DLBCL which presents as a heterogeneous disease group with variable outcomes [87]. In our metaanalysis, the individual studies that showed a significantly increased risk of DLBCL (OR > 1), analyzed populations exposed to solvents (benzene, formaldehyde, chloroform, carbon tetrachloride, dichloromethane, dichloroethane, and methyl chloride) [64,70] and hair dyes [66]. In addition, one study carried out their investigations with meat handlers, people in contact with meat and meat products in general (contact with beef, chicken, pork, lamb, meat from other animals and fish), [73] and another study with the agricultural occupations (farm workers and cattle or animal breeders) [66] (Figure 4B). Few meta-analysis studies separately assess the DLBCL subtype associated with any given type of exposure. One of the compounds evaluated by the articles that showed significant OR in our metaanalysis for the DLBCL subtype was benzene. Rana et al. [88] found an association between benzene exposure and an increased risk of DLBCL in their meta-analysis.
The remaining meta-analyses for the remaining subtypes generated meta-OR above the null value of 1.0, yet, with no significance ( Figure S3). Some meta-analysis studies assessed the increased risk of NHL subtypes associated with exposures to chemical compounds. Similar to our study, increased risks of MM (OR = 1.16; 95% CI = 0.99-1.36) were detected in association with pesticide exposure [89] and trichloroethylene [90], however, without statistical significance. MM risk was also not significant for occupational exposure to polycyclic aromatic hydrocarbons [91]. On the other hand, in the meta-analysis by Chang and Delzell [92], they found significant meta-relative risks for the association between glyphosate and MM, however, for the subtypes DLBCL, LLC/SLL, FL, and Hairy Cell Leukemia, no significant association was observed.
A significant association between exposure to any single solvent and the risk of FL was also identified [21]. In our study, the meta-analysis for FL showed positive association (OR > 1) however, of no significance (OR = 1.17, CI: 0.95-1.44). We did observe a significant association for individual studies, including two studies that evaluated solvent exposure [63,68] (Figure S3C). Many studies have also demonstrated an association between benzene exposure and subtypes of NHL. Benzene exposure has been associated with an increased incidence of Cutaneous T Cell Lymphoma [93], and CLL [9].
When analyzing the different types of study designs, only the case-control studies analysis revealed a meta-OR above 1.0 with significance for the random-effects model (OR 1.21, 95% CI 1.03-1.41), while for the meta-analysis performed with the cohort studies, the meta-OR was less than 1.0 and non-significant (OR 0.82, 95% CI 0.36-1.92) ( Figure S4). For the subgroup analyses by exposure type, three meta-analyses were performed, one considering studies that evaluated only work class, another evaluating only chemical compounds, and a third addressing only those articles that investigated both work class and exposure to chemical compounds (Figures 5-7). The remaining meta-analyses for the remaining subtypes generated meta-OR above the null value of 1.0, yet, with no significance ( Figure S3). Some meta-analysis studies assessed the increased risk of NHL subtypes associated with exposures to chemical compounds. Similar to our study, increased risks of MM (OR = 1.16; 95% CI = 0.99-1.36) were detected in association with pesticide exposure [89] and trichloroethylene [90], however, without statistical significance. MM risk was also not significant for occupational exposure to polycyclic aromatic hydrocarbons [91]. On the other hand, in the meta-analysis by Chang and Delzell [92], they found significant meta-relative risks for the association between glyphosate and MM, however, for the subtypes DLBCL, LLC/SLL, FL, and Hairy Cell Leukemia, no significant association was observed.
A significant association between exposure to any single solvent and the risk of FL was also identified [21]. In our study, the meta-analysis for FL showed positive association (OR > 1) however, of no significance (OR = 1.17, CI: 0.95-1.44). We did observe a significant association for individual studies, including two studies that evaluated solvent exposure [63,68] (Figure S3C). Many studies have also demonstrated an association between benzene exposure and subtypes of NHL. Benzene exposure has been associated with an increased incidence of Cutaneous T Cell Lymphoma [93], and CLL [9].
A meta-analysis, which included studies that analyzed only work class, did not exhibit significantly increased risk of NHL (OR 1.22, 95% CI 0.91-1.64) (Figures 5A and S5). Despite not showing significant OR, five individual study results did show significant OR, among which, four assessed individuals in agricultural occupations [11,12,42,66] and one, of employees exposed to meat [71]. Furthermore, based on this analysis, NHL, B-Cell Lymphoma, DLBCL, FL, T-Cell, MM, CLL, SLL, and T/NK Cell, were the subtypes of NHL addressed by the studies that presented a significantly increased risk of NHL. These results illustrate the potential risks posed by these two classes of work concerning the development of NHL regardless of subtype, however, further studies are needed ( Figure 5B).
For the meta-analysis that included studies that examined only chemical compounds, significantly increased risk of NHL was observed (OR 1.24, 95% CI 1.06-1.46) (Figures 6A and S6). In this analysis, it was found that the studies with significant OR evaluated overall NHL, as well as the subtypes of DLBCL, FL, and CLL. Nine individual study results displayed significant OR, of which, five of the studies examined occupational exposure to pesticides [7,37,40,78,81]. A positive association between occupational exposure to some pesticides and the development of NHL was verified in the review study by Schinasi and Leon [94], in which they provided consistent evidence of this relationship. Exposure to glyphosate-based herbicides, 2,4-D and diazinon were also associated with increased risk of NHL in humans [22,46,47].
In addition to pesticide exposure, exposure to solvents, such as benzene (n = 1) [48], trichloroethylene (n = 1) [63], and solvents overall (n = 1) [68] (Figure 6B), was likewise observed in the studies. There is some evidence concerning the role of benzene in increasing the risk of NHL. In the meta-analysis studies by Rana et al. [88] and Steinmaus et al. [95], a causative link between benzene exposure and the development of NHL was evidenced. In contrast, the meta-analysis by Kane and Newton [96] found no association between benzene exposure and the increased risk of NHL or any subtype. Some studies have already demonstrated an association between exposure to trichloroethylene and the increased risk of NHL [63,93,97]. Our meta-analysis did not assess the individual association of compounds with the increased risk of NHL; however, we did find that these solvents were compounds evaluated in the studies that displayed a significant OR in our meta-analysis.
The meta-analysis that included studies that examined both work class and chemical compounds did exhibit a significantly increased risk of NHL (OR 1.21, 95% CI 1.08-1.36) (Figures 7A and S7). The studies that showed significant OR in this analysis evaluated only the development of general NHL and/or MM and CLL subtypes. As for the exposure assessed in each of these studies, one of the studies looked at factory employees exposed to benzene along with the compound benzene [58]; another study evaluated individuals from the agricultural occupation, in addition to, pesticides, mercury, and formaldehyde [60]; there was another study with employees employed in aircraft manufacturing with exposure to chromate compounds, trichloroethylene, perchloroethylene, and mixed solvents [62]; and a further study included agricultural workers, and assessed exposure to pesticides and naphthalene [77] ( Figure 7B).
Subgroup analyses such as NHL subtype, study design, and exposure type did not reveal the leading sources of heterogeneity observed in our overall meta-analysis (Figures 3 and S1). Nevertheless, considering the variety of NHL subtypes, the different possible settings for exposure (work class and chemical agents), exposure assessment methods, statistical results, study population, study site, and other factors evaluated in the studies included in our meta-analysis, we had already anticipated a high heterogeneity. In summary, despite the heterogeneity between studies in the different analyses performed and in our overall meta-analysis ( Figure S1), we conclude that the synthesis of evidence from the epidemiological literature supports an increased risk for NHL. This result is independent of the subtype of NHL and the type of occupational exposure and compounds evaluated.

Strengths
Our meta-analysis synthesized 51 epidemiological studies examining the relationship between chemical agents and work classes and the risk of NHL. To the best of our knowledge, this is the first and largest systematic review with meta-analysis that takes into account all exposure types (chemical agents and/or work class) and all subtypes of NHL. Overall, our results provide evidence for the hypothesis that occupational exposure to chemical agents increases the risk of NHL. Thus, these results represent an important contribution to the literature on exposures associated with the development of NHL.

Limitations
A limitation of the study is that our review was conducted with studies published between 2000 and 2020 (which included mature B-, T-, and NK-cell neoplasms as well as CLL and multiple myeloma as subtypes of LNH). However, according to the new classification of the World Health Organization to Hematolymphoid Tumors: Lymphoid Neoplasms (5th edition), the term LNH is no longer used [98]. The 51 studies that were reviewed in the analysis were quite heterogeneous, leading to high heterogeneity in the overall and subgroup meta-analysis. Although we examined possible sources of heterogeneity using factors such as NHL subtype, exposure type, and study design, there may be other possible causes of heterogeneity that could not be assessed. Adjustment for confounding factors such as anthropometric and sociodemographic variables was not performed, as most of the studies included had adjusted their risk measure for such factors. It is important to note that people are subject to both occupational and environmental exposure to a mixture of chemical compounds, causing the exposure profile to not be fully characterized in individual studies, and thus some of the observed associations may be due to chance. A further limitation of our study is that exposure, in most of the studies, was assessed by self-reported responses to epidemiologically applied questionnaires, which have the potential for memory bias and measurement error and not by objective and standardized measurements for exposure.

Conclusions
In this systematic review through meta-analysis, we present the evidence, through a detailed evaluation of epidemiologic studies, supporting the association between occupational chemical exposure and the risk of developing non-Hodgkin lymphoma. We demonstrate that the risk of NHL, regardless of the subtype, increases for individuals occupationally exposed to chemical agents, mainly pesticides, benzene, and trichloroethylene, as well as for certain work classes, primarily for occupations in agriculture. However, there is still insufficient data on the association between NHL and specific chemical compounds. Our findings may provide information for public health and practical decision-making about certain work activities and the use of chemical compounds. Furthermore, the evidence for the association of specific chemical compound classes and work classes associated with the development of NHL in biological samples is still limited, so future mechanistic studies, measuring exposures, and evaluating the biological and molecular effects associated with the risk of NHL are still needed.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/cancers15092600/s1, Figure S1: Funnel Plot of the studies included in the overall meta-analysis. Each dot represents one study; Figure